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United States Patent SUBSTITUTED LItD-DIAZA-ANTHRACENES Alan AugustGoldberg, Shepton Mallet, England, assignor t Ward Blenkinsop & CompanyLimited, London,'England, a British company No Drawing. Application July1955, Serial No. 520,097

Claims priority, application Great Britain July 8, 1954 12 Claims. (Cl.260-288) in which R is an alkoxy group having one to six carbon atomsand preferably containing not more than four carbon atoms, Y is ahydrogen or halogen atom, R is a monoor di-hydroxy alkyl group having atleast two but not more than six carbon atoms, and preferably containingnot more than four carbon atoms, and n is an integer having a minimumvalue of two and a maximum value of six, and is preferably two, three orfour. The invention also includes the acid salts of the said9-substituted- 1 .10-diaza-anthracenes.

The group R may be an omega=hydroxy straight chain alkyl group havingtwo to six carbon atoms such as p-hydroxyethyl; it may also be astraight chain alkyl group carrying the hydroxyl group on a carbon atomother than the terminal carbon atom, such as fl-hydroxyn-propyl or'y-hydroxy-n-butyl: itmay also be a branched chain alkyl group carryingan hydroxyl group such as fl-hydroxy-iso-butyl: or it may be a dihydroxyalkyl group such as B,v-dihydroxy-n-propyl.

In accordance with a feature of the invention the said9-substituted-1.l0-diaza-anthracenes are produced by heating a9-substituted-1.IO-diaza-anthracene having, in one tautomeric form, thegeneral formula NH2.(CH2)n.NHR'

in which R and n are as above defined.

The 1.10-diaza-anthracenes which form the starting material for thepresent process and contain a halogen 2,775,595 a ented ec. 2.5,

atom in the 9-position may be produced as disclosed in British patentspecification No. 704,238. The 9-phenoxy compounds may be produced fromthe 9-halogeno compounds by heating the latter with phenol, a cresol, axylenol or other polyalkylphenol or a mixture of two or more of suchcompounds. The resulting 9-phenoxy compound or mixture of 9-phenoxycompounds may be used as produced in situ or may be first isolated ifdesired. The reaction may be carried out in the presence of an inertsolvent: in the case of the 9-phenoxy compounds an excess of the phenolor phenols used to produce the compound or compounds may constitute theinert solvent. Specific examples of compounds which may be employed are2 methoxy 9 chloro 1.10 diaza anthracene, 2 methoxy 9 phenoxy 1.10 diazaanthracene, 2 methoxy 6.9 dichloro 1.10 diaza anthracene, 2 methoxy 6chloro 9 phenoxy 1.10 diaza anthracene, 2 n butoxy 6.9 dichloro 1.10diaza anthracene and 2 n butoxy 6 7 chloro 9 phenoxy 1.10- diazaanthracene.

Examples of hydroxy amines having the general forrnula NHz(CH2)n.NHRwhich may be employed include 2 (2' hydroxyethylamino) ethylamine, 3 (2hydroxyethylamino) n propylamine, 2 (2 hydroxyn propylamino) ethylamine,3 (2 hydroxy n propylamino) propylamine, 3 (3" hydroxy n butylamino) npropylamine, 2 (2 hydroxy iso butylamino) ethylamine, 2 (2.3' dihydroxyn propylamino) ethylamine and 3 (2.3' dihydroxy 11 propylamino) npropylarnine.

When Z is a halogen atom the 9-halogeno-Ll0-diazaanthracene may beheated with the hydroxy amine having the general formula NH2(CH2)n,NHR'in the presence or absence of an inert solvent.

When Z is a phenoxy group the phenoxy compound may be first prepared byheating the 9-haloge'no-L10- diaza-anthracene with phenol, a cresol, axylenol or other polyalkylphenol or a mixture of two or more suchcompounds and the hydroxyamine then added or alternatively the phenoland the hydroxyamine may be heated together with the9-halogeno-1.10-diaza-anthracene. Alternatively the phenoxy compound maybe prepared as outlined above and isolated before heating with thehydroxyamine.

The new compounds in the form of the free bases may be isolated bypouring the cooled reaction mixture into an excess of aqueous causticalkali, separating the product and crystallizing from a suitablesolvent. The free bases may also be produced by neutralization of theirhydrohalide salts. They can be crystallized from basic solvents such aspyridine and the alkyl pyridines.

The new compounds in the form of their hydrohalide salts may be readilyisolated from reaction mixtures in which the9-halogeno1.l0sdiazo-anthracene has been heated with the hydroxyamine inthe presence or absence of a phenol, cresol, xylenol or mixture of twoor more such compounds by pouring the cooled reaction mixture into alarge volume of anhydrous ether, acetone or methyl ethyl ketone andcollecting the precipitate of the monohydrohalide of the base. Themonohydrohalide may be readily recrystallized from the correspondingdilute aqueous hydrogen halide to yield the dihydrohalide of the baseand may also containone or more molecules of water of crystallization.Since it is preferred to employ the 9-chloro-LIOTdiaZa-anthracene in theprocess this method readily lends itself to the production of themonoand di-hydrochlorides of the new bases.

The new compounds and their salts have been found to possess valuablepharmacological properties. They are useful in the treatment of avariety of helminth infections both in human beings and in animals andare of low toxicity.

The following examples illustrate the nature of the invention and themanner in which it may be performed:

Example 1 28. gms. of 2-methoxy-.6.9-dichloro-1.IO-diaza-anthracene isheated with 100 gms. of dry phenol for 1 hour. To the resulting reactionmixture is added 16 gms. of 2- (2'.3-dihydroxy-n4propylamino)-ethylamine(obtained by the interaction of ethylene diamine with glycerolocmonochlorohydrin) and the mixture heated at 110-115 C. for a further 1/2 hours. The reaction mixture is then allowed to cool, poured into 300cc. of acetone containing 12.5 cc. of 10.N. hydrochloric acid and themixture allowed to stand overnight. The resulting yellow precipitate iscollected, washed first with ether and then with acetone, then dissolvedin 400 cc. of boiling water and the solution filtered with charcoal. Thefiltered solution is reheated to about 80 C. and 200 cc. of Nhydrochloric acid added thereto: bright yellow microcrystalline needlescommence to separate. The mixture is quickly chilled and after severalhours the needles, which are 2-methoxy-6-chloro-9-[2(2".3-dihydroxy-npropylamino)-ethylamino] 1.10-diaZa-anthracenedihydrochloride, are collected (yield 27 gms.) and are found to have amelting point of 264-268 C. Found: N, 12.6%; CI, 24.0%: CmHzsOsNrCl;requires N, 12.5%; CI, 23.8%.

The LD 50 value of this compound when administered orally to mice is 800mg./kg. It is very active against human schistosomiasis whenadministered in a dosage of the order of 12 mg./kg. per day for fiveconsecutive days or in a lesser dosage for a longer period.

Example 2 A solution of 28 gms. of 2-methoxy6.9-dichloro-1.10-diaza-anthracene in 200 gms. of phenol is heated to 110- 115 C. for 1hour. 2 gms. of 2-(2-hydroxypropylamino-ethylamine is added and theresulting solution heated at the same temperature for 2 hours, cooled,and poured into 700 cc. of acetone containing 12 cc. of 10 Nhydrochloric acid. After keeping overnight in the re frigerator theyellow precipitate is filtered oif, washed with dry acetone, anddissolved in 400 ccs. of boiling water. The solution is filtered withcharcoal, reheated to about 80 C., and 100 cos. of saturated aqueousammonium chloride added: after keeping overnight, the yellowmicro-crystalline precipitate of 2-rnethoxy6- ch1oro-9-[2-(2"-hydroxypropylamino) ethylamino] 1.10-diaza-anthracene dihydrochloride (32 g.;M. P. 264 C.) is filtered off and dried at 60 C.

It can be recrystallized by dissolving 20 gms. of the salt in 200 ccs.of boiling water and then adding 20 ccs. of 10 N hydrochloric acid; thedihydrochloride slowly separates in clusters of small yellow aggregates,M. P. 266268 C. (Found: N, 12.6; CI, 24.3. C1sH21ON4Cl. 2HC1.1H2Orequires: N. 12.8; C1, 24.4%.)

Example 3 By using 32 gms. of2-n-butoxy-6.9-dichloro-l.IO-diazaanthracene in place of the 28 gms. ofthe corresponding Z-methoxy-derivative in Example 2, there is obtainedin like manner 36 gms. of 2-n-butoxy-6-chloro-9-[2'-(2"-hydroxypropylamine) ethylamino] 1.10 diazaanthracene dihydrochloridein the form of a bright yellow microcrystalline powder.

Example 4 A solution of 28 gms. of 2-methoxy-6.9-dichloro-1.10-diaza-anthracene in 200 gms. of phenol is heated at 110 C. for 1 hour.11 gms. of 2-(2-hydroxyethylamino)- ethylamine is added and the mixtureheated for 2 hours at 115 C., cooled and poured into 700 ccs. of acetonecontaining 12 ccs. of 10 N hydrochloric acid. After keeping overnight,the yellow precipitate is collected, washed with acetone and dissolvedin 400 ccs. of boiling water. The solution is filtered with charcoal,reheated to about C. and diluted with ccs. of saturated ammoniumchloride solution; 2-methoxy-6- -chloro-9- [2-(2"1hydroxyethylamino-ethylamino] -1. l0- diaza-anthracene dihydrochloride (30 gms.) slowlyseparates as a yellow microcrystalline powder, M. P. 280 C. (Found: N,12.8; Cl, 24.1. C17H19ON4CL2HCL2H2O requires: N, 12.8: C1, 24.4%.)

On order to obtain the free base a warm aqueous solution of thedihydrochloride is poured into an excess of stirred cold N sodiumhydroxide, the yellow precipitate collected and washed with water. Thefree base crystallizes from dilute pyridine in bright yellow needles, M.P. 172 C.

Example 5 By using 15 gms. of 3-(2'.3-dihydroxypropylamino)- propylaminein place of the 2-(2'-hydroxyethylamino)- ethylamine in Example 4, thereis obtained in like manner 27 gms. of2-methoxy-6-chloro-9-[3-(2.3"-dihydroxypropylamino)propylamino1-1.lO-diaza-anthracene dihydrochloride as a yellowmicro-crystalline powder, M. P. 220 C.

Example 6 By using 24.4 gms. of 2-methoxy-9-chloro-1.10-diazaanthracenein place of the 28 gms. 2-methoxy-6.9-dichloro-l.IO-diaza-anthracene inExample 4 there is obtained in like manner 27 gms. of2-methoxy-9-[2'-(2"- hydroxyethylamino)-ethylamino] -l .IO-diazaanthracene dihydrochloride as a bright yellow micro-crystalline powder.

I claim:

1. A 9-substituted LIO-diaZa-anthracene having, in one tautomeric form,the general formula in which R is an alkoxy group having one to sixcarbon atoms, Y is selected from the group consisting of hydrogen andhalogen atoms, R is an hydroxy-alkyl group having at least two but lessthan seven carbon atoms and at least one but less than three hydroxylgroups and n is an integer having a minimum value of two and a maximumvalue of six, and acid salts thereof.

2. A 9-substituted 1.10-diaza-anthracene having, in one tautomeric form,the general formula 3. A 9-substituted 1.10-diaza-anthracenc having, inone tautomeric form, the general formula in which R is an alkoxy grouphaving one to six carbon atoms, R is an hydroxy-alkyl group having atleast two but less than sevencarbon atoms and at least one but less thanthree hydroxyl (gro ps and ,n i an. integer having a minimum value oftwo and a maximum value of six, and acid salts thereof.

4. A 9-substituted 1.10-diaza-anthracene having, in one tautomeric form,the general formula in which R is an alkoxy group having one to sixcarbon atoms.

5. A 9-substituted 1.10-diaza-anthracene having, in one tautomeric form,the general formula NH.CHn.CH2CH2.NH.CHn-CHOH.CH2OH in which R is analkoxy group having one to six carbon atoms.

6. 2 methoxy 6 chloro 9 [2' (2".3" dihydroxyn-propylamino)-ethylamino]-1.10-diaza-anthracene.

7. 2 methoxy 6 chloro 9 [2' (2" hydroxy npropylamino)-ethylamino]-1.l-diaza-anthracene.

8. 2 n butoxy 6 chloro 9 [2' (2" hydroxy npropylamino)-ethylamino]-1.IO-diaza-anthracene.

9. 2 methoxy 6 chloro 9 [2 (2 hydroxyethylamino -ethylamino] -l lO-diaza-anthracene.

10. 2 methoxy 6 chloro 9 [3 (2".3" dihydroxypropylamino -propylamino]-l.10-diaza-anthracene.

11. A process for preparing a 9-substituted 1.10-diazaanthracene having,in one tautomeric form, the general formula IITHXOHa) n-NHR' in which Ris an alkoxy group having one to six carbon atoms, Y is selected fromthe group consisting of hydrogen and halogen atoms, R is an hydroxyalkyl group having at least two but less than seven carbon atoms and atleast one but less than three hydroxyl groups and n is an integer havinga minimum value of two and a maximum value of six which comprisesheating a 9-substituted LIO-diaZa-anthracene having, in one tautomericform, the general formula in which R and Y are as above defined and Z isselected from the group consisting of halogen atoms and phenoxy,alkylphenoxy and polyalkylphenoxy groups, with a hydroxyamine having thegeneral formula in which R and n are as above defined, and isolating theproduct.

12. A process for preparing a 9-substituted 1.10-diazaanthracene having,in one tautomeric form, the general formula in which R and Y are asabove defined and Z is selected from the group consisting of halogenatoms and phenoxy, alkylphenoxy and polyalkylphenoxy groups, with ahydroxyamine having the general formula NHz. CH2) 11,.NHR'

in which R and n are as above defined, and isolating the product.

No references cited.

1. A 9-SUBSTITUTED 1.10-DIAZA-ANTHRACENE HAVING, IN ONE TAUTOMERIC FORM,THE GENERAL FORMULA